Europe faces up to big pharma over clinical data

Is 2014 the year that Europe gets drug companies to publish all their data on the safety and effectiveness of medicines?

The hazards of medicines are not trade secrets

(Image: Chassenet/SPL)

Next week could see a major step forward in the battle to pass laws compelling drug companies to release all the data from their clinical drugs trials. On 12 March, the European Parliament is expected to finalise and give formal approval to much amended draft legislation, with a full vote taking place at the beginning of April.

But even as members deliberate, pharmaceutical companies will be fighting back in the European Court of Justice against the European Medicines Agency (EMA), the European Union agency with responsibility for regulation of medicines in Europe. Its recent actions have paved the way for the proposed legislation. Two court cases brought by US-based companies, AbbVie (an offshoot of Abbott) and the biotech firm InterMune, are a powerful reminder that the road towards scientific transparency is strewn with rocks.

Those who back the proposed legislation hope that the outcomes will achieve linked ends. Every year millions of people die or are harmed by adverse reactions to medicines, drugs prescribed in good faith by their doctors. In calling for full and open disclosure of all the scientific evidence, the law should lead to safer medicines and therefore to safer prescribing. Disclosure also serves the true interests of advancing collective knowledge, allowing the science underpinning drug development to flourish.

Currently, drugs manufacturers publish only some of the data, on the grounds of commercial confidentiality. Many negative trials fail to see the light of day, and this causes a systematic misrepresentation of medicines, making them seem more effective and safer than they actually are.

No negatives

Take antidepressants, where one paper found that positive trials submitted to the US Food and Drug Administration (FDA) for approval were 12 times as likely to be published in a way that agreed with the FDA analysis as were studies with negative results. And even published reports often fail to tell the full story.

Late last year, the Institute for Quality and Efficiency in Health Care (IQWiG), an independent German agency responsible for assessing the quality and efficiency of medical treatments, including drugs, compared 101 trial reports in medical journals on drugs for a range of chronic diseases with the full clinical study reports submitted to regulators. The journal articles reported on less than 25 per cent of measured outcomes and 70 per cent failed to report even on deaths.

Until recently, regulators have been complicit in preventing public access to full trial reports. But last year, the EMA began to change the game, releasing previously secret documents, and laying the groundwork for the potential new law. But the two court cases currently at the European Court of Justice threaten to close down this access to information.

The EMA’s commitment to transparency dates back to 2010, when the European Ombudsman ruled against the agency after it refused to provide trial reports on anti-obesity medicines to researchers from the Nordic Cochrane Centre, part of the global, independent Cochrane Collaboration network, which aims to promote and facilitate evidence-based healthcare.

Empowering citizens

The Cochrane research group was carrying out a systematic review of these medicines and appealed to the Ombudsman, arguing that they needed all the relevant scientific evidence, including the full clinical study reports submitted to the EMA. An Irish law firm name also appealed to the Ombudsman following the EMA’s refusal to release data on an acne treatment.

The Ombudsman ruled against the EMA in both cases, judging that public access to information “empowers citizens to monitor and scrutinise effectively the exercise of the powers vested in the EU institutions”. Not only should the EMA provide access in these cases and in response to requests, said the Ombudsman, but it should proactively release information.

Since this ruling, the EMA has taken unprecedented steps to make full clinical study reports and anonymised individual patient data available. The agency has already released millions of pages of documents in response to requests, and the proactive release of data is expected after a management review later this month.

The agency has recently reiterated its intention to proceed with these changes despite the challenges from AbbVie and InterMune. These cases involve AbbVie’s rheumatoid arthritis drug adalimumab (Humira) and InterMune’s pirfenidone (Esbriet), which is used to treat the fatal lung disease idiopathic pulmonary fibrosis. The companies argue that releasing data will provide competitors with an unfair advantage.

Conflict of interests

Both cases, however, also highlight the tension between commercial and public interests. Adalimumab was the world’s best-selling medicine in 2012, with sales worth &dollar;9.3 billion. It was the third drug approved in its class, after infliximab (Remicade) and etanercept (Enbrel).

But an independent French medical bulletin, Prescrire, described it as “nothing new” when first approved as a rheumatoid arthritis treatment, for patients who have failed on previous therapy, no more effective than etanercept as monotherapy, and at best “possibly helpful” when used in combination with methotrexate, although it is considerably more expensive than infliximab and etanercept. All three drugs increase the risk of lymphoma and serious infections.

InterMune’s pirfenidone is approved in Europe and Canada, but not the US. The FDA, the federal body which regulates prescription medicines in the US, judged that one of two large trials failed to show an advantage over placebo. Prescrire notes a lack of evidence in these two trials that pirfenidone improves quality of life or slows progression of the disease, while its many side effects are well documented.

An initial injunction prevented the EMA from releasing any documents on these products, but on 5 December 2013, the European Court of Justice upheld the EMA’s appeal against this injunction. To maintain secrecy, the companies must now provide evidence, document by document, that release would lead to serious and irreparable harm.

Step forward

Guido Rasi, head of the EMA, applauded the decision&colon; “Although we have not won the case yet, this is a first important result since the litigation started.”

Meanwhile, also in December, the European Parliament and COREPER, one of the EU bodies negotiating legislation, agreed on a draft legislation requiring all trial data to be placed in an accessible database and specifying that study protocols and full clinical study reports should be made public after approval. The draft also addresses other problems with the evidence, requiring studies to be carried out in vulnerable population groups, such as the frail elderly, and encouraging trials by non-commercial organisations.

These provisions underline the fact that transparency is no panacea by itself. Trials need to be designed to address the right questions, and ideally there should be a firewall between testing drugs for effectiveness and safety, and commercial interests, with no direct company involvement in the design or conduct of trials. Transparency in clinical trials is a crucial first step, however. The European Court of Justice’s ruling on these two legal cases, expected in 2015, is likely to be pivotal. We can only hope that science and the public interest prevails.

By Barbara Mintzes

Barbara Mintzes is assistant professor at the School of Population and Public Health, University of British Columbia, Vancouver